Olanzapine is an antagonist of dopamine at D-1 and D-2 receptors and has antimuscarinic anti-cholinergic properties and antagonist activity at 5HT-2 receptor sites. Olanzapine also has antagonist activity at noradrenergic alpha-receptors. The above-identified properties indicate that olanzapine is a potential neuroleptic with relaxant, anxiolytic, or anti-emetic properties, and is useful in treating psychotic conditions such as schizophrenia, schizophreni-form diseases, and acute mania. At lower doses olanzapine can be used in the treatment of mild anxiety states. Olanzapine has also been reported as having a high level of activity in the clinical evaluation of psychiatric patients suffering from schizophrenia and it exhibits this high activity at surprisingly low dosage levels.
Olanzapine has shown great promise in the treatment of psychotic patients. Unfortunately, olanzapine typically exhibits a color which is undesirable for commercial pharmaceutical use, especially since the color was found to change over time on exposure to air. Carbon treatment of olanzapine did not removed the undesired color. A pharmaceutical that changes color over time could be particularly troublesome for psychotic patients if a dosage form, such as a tablet, was chosen where color changes were apparent. Consequently, there have been many attempts to provide novel olanzapine polymorphs.
Polymorphic forms and hydrate/solvate forms of olanzapine have been disclosed in various patents and publications. For example, U.S. Pat. No. 5,736,541 (“the '541 patent”) and EP Patent No. 733 635 disclose olanzapine Form II, an anhydrate, however, as disclosed Form II may be difficult to prepare in the absence of technical grade olanzapine or alternative methods for preparing olanzapine. The '541 patent discloses that the prior known Form I of olanzapine, as prepared by the procedures described in U.S. Pat. No. 5,229,382, is metastable and unsuitable for commercial use due to discoloration of the compound over time. U.S. Pat. No. 5,637,584 discloses a monosolvate of dichloromethane identified as Form I, however as discussed above, Form I may be unsuitable for commercial use. U.S. Pat. No. 5,703,232 and EP Patent No. 733,634 disclose olanzapine, which while free of water and acetonitrile, contains solvates of methanol, ethanol, and isopropanol. U.S. Pat. No. 6,020,487 and EP Patent No. 831,098 disclose dihydrate forms of olanzapine, selected from dihydrate B, dihydrate D, and dihydrate E, which may be used for the preparation of anhydrate olanzapine. Each of the above-identified patents identifies a different crystalline form of olanzapine as identified by X-ray diffraction peaks and their relative intensities.
U.S. Pat. No. 6,348,458 discloses Form III, Form IV, and Form V olanzapine, which are anhydrates produced under aqueous conditions. Form III, Form IV, and Form V olanzapine are synthesized by dissolving olanzapine in mineral acid, followed by reaction with base, and precipitation of the crystalline form. PCT publication WO 02/18390 discloses olanzapine as monohydrate-I and dihydrate-I and WO 02/060906 discloses olanzapine as Form X. In addition to X-ray powder diffractions, FTIR or DSC were used to identify the crystalline olanzapine.
Despite the many attempts by the prior art, there is a need to obtain desirable olanzapine crystals with fewer purification steps, that lacks the harshness of mineral acids, or additional synthetic steps. The present invention provides novel crystalline forms of olanzapine that avoid the synthetic and purification pitfalls of the prior art.